The structure and function of synapses in Down syndrome (DS) brain are abnormal, causing the cognitive deficits that characterize this developmental disorder. Research within the last decade has revealed that, in addition to pre- and post-synaptic neurons, astrocytes are critical to synapse formation and plasticity. Astrocytes control dendritic growth, synaptogenesis, synapse function, and synaptic plasticity. The role of astrocytes in DS synapse development has not been studied in either humans or in mouse models of DS. The objective of this R03 application is to investigate whether DS astrocytes contribute to the defective synapse formation and function in DS. The experiments will utilize both cells from a DS mouse model (Ts65Dn) and human trisomy 21 cells, to define the contribution of astrocytes to dendritic growth, synapse number, and synapse function in DS. Results from these pilot experiments will provide insight into the fundamental development of DS synapses, and will form the basis for further studies to define the nature of the astrocyte support as well as test potential therapeutic strategies to improve synaptic development in DS. PROJECT NARRATIVE: As the most common genetic cause of mental retardation, Down syndrome is a public health concern. The proposed research will focus on the communication among nerve cells in Down syndrome as the brain develops. The aim of the research is to define the role of astrocytes, or support cells, in shaping the communication among nerve cells, and whether they are dysfunctional in Down syndrome.